Role of the Heme Axial Ligand on the Reactivity of High-Valent Oxo-Iron Porphyrin Intermediate

High-valent iron oxo species have been known as the key reaction intermediates in the catalytic cycles of oxygen activating iron enzymes.  In heme enzymes, oxoiron(IV) porphyrin π-cation radical species named compound I were characterized in the catalytic cycles of peroxidases, catalases, and cytochrome P450.  These heme enzymes have the same heme (iron protoporphyrin IX), but different heme proximal (axial) ligands; histidine in peroxidase, tyrosine in catalase, and cysteine in cytochrome P450, which are highly conserved in these heme enzymes.  Therefore, the axial ligand has been believed to tune the reactivity of compound I.  To reveal functional role of the axial ligand, the axial ligand effect on the reactivity of high-valent iron oxo species has been studied systematically with synthetic enzyme model complexes.  In this presentation, we present how the heme axial ligand modulate the reactivity of compound I.  Compound I model complexes, (TMP^+·)Fe^IVO(L), changed its reactivity by identity of the axial ligand, but the reactivity did not correlate with any spectroscopic data of (TMP^+·)Fe^IVO(L), such as the redox potential and Fe=O bond strength.  Surprisingly, a clear correlation was found between the reactivity of (TMP^+·)Fe^IVO(L) and Fe^II/Fe^III redox potential of (TMP)Fe^IIIL, the final reaction product.  Axail ligand-exchange experiments and theoretical calculations showed linear free-energy relationship, in which the axial ligand modulates the reaction free energy by changing the stability of (TMP)Fe^III(L) more significantly than (TMP^+·)Fe^IVO(L).  All results indicate that the reactivity of compound I is controlled by thermodynamic stability of the ground state of the final reaction product, not but compound I itself.  Therefore, the heme axial ligand activates compound I by stabilizing the resting state, not by activating compound I.  The proposed mechanism can be explained by the trans-ligand effect of the oxo-ligand, which migrates from compound I to substrate in the reaction.